Interleukin 1 receptor-associated kinase 1 (IRAK1) mutation is a common, essential driver for Kaposi sarcoma herpesvirus lymphoma.

Primary effusion lymphoma (PEL) is an AIDS-defining cancer. All PELs carry Kaposi sarcoma-associated herpesvirus (KSHV). X chromosome-targeted sequencing of PEL identified 34 common missense mutations in 100% of cases. This included a Phe196Ser change in the interleukin 1 receptor-associated kinase 1 (IRAK1). The mutation was verified in primary PEL exudates. IRAK1 is the binding partner of MyD88, which is mutated in a fraction of Waldenström macroglobulinemia. Together, these two mediate toll-like receptor (TLR) signaling. IRAK1 was constitutively phosphorylated in PEL and required for survival, implicating IRAK1 and TLR signaling as a driver pathway in PEL and as a new drug development target.